Activation of an invasive program is a critical event in the multi-step process of tumor metastasis driven by the activation of tyrosine kinases and ligand-stimulated chemokine receptors. We now show that the Abl family of nonreceptor tyrosine kinases, Abl (Abl1) and Arg (Abl2), which are activated downstream of multiple receptor tyrosine kinases (RTKs), are also activated by chemokine receptors and play a critical role in the regulation of cancer cell invasion. We show that Abl kinases are required for epithelial cancer cell invasion and matrix degradation and identify a novel signaling pathway that links the Abl kinases to the regulation of the matrix metalloproteinase MT1-MMP in breast cancer cells. Moreover, we found that endogenous Abl kinases are hyperactivated in a subset of breast cancer cell lines that are negative for Her2 and hormone receptors. Further, expression of activated Abl kinases elicits a striking disruption of epithelial cell polarity which is associated with cancer progression. Based on these findings, we hypothesize that Abl kinases are required for metastasis of a subset of epithelial tumors through regulation of invasive programs and thus combination therapies that target inhibition of Abl kinases might be exploited for the treatment of a subset of invasive breast tumors. To this end we propose the following aims: 1) Identify the phosphoproteomic signature for activated Abl kinases in human breast cancer cells. Knowledge of the molecular signature induced by activated Abl kinases in breast tumors will allow for identification of patients that might benefit from targeted therapy with approved and novel Abl kinase inhibitors;2) Elucidate the mechanisms employed by Abl kinases to regulate breast cancer cell invasion;and 3) Define the role of Abl kinases in mammary tumor progression and metastasis using mouse models. Together these aims will uncover Abl-dependent signaling networks that regulate invasive programs that drive cancer tumor progression and metastasis. The long-term goal of these studies is to develop novel therapeutic approaches with greater specificity and reduced toxicity than those provided by current therapies for the treatment of specific tumor subtypes. Inhibition of the Abl kinases is expected to simultaneously block multiple signaling pathways required for tumor invasion that converge on the activation of these unique kinases. PUBLIC HEALTH RELEVANCE: Disruption of cell polarity and activation of an invasive program are critical events in the multi-step process of tumor metastasis. We have identified the Abl family of nonreceptor tyrosine kinases as critical regulators of cell polarity and cancer cell invasion. We found that Abl kinases, which are activated downstream of multiple RTKs, are also activated downstream of chemokine receptors in breast cancer cells and are required for cancer cell invasion and matrix degradation. Results from the proposed studies have wide-ranging implications for the development of novel therapeutic approaches with greater specificity and reduced toxicity than current therapies for the treatment of invasive solid tumors. Inhibition of the Abl kinases will result in the simultaneous block of multiple signaling pathways required for the invasion of epithelial tumors driven by the activation of RTKs and/or chemokines that converge on the activation of these unique kinases.